The overall goal of this five-year competitive renewal application is assessment of the therapeutic value of cardiac transplantation in patients with advanced forms of heart disease. Individual scientific objectives are contained within four major projects. The first is directed toward correlative analysis of preoperative immunological parameters with specific donor-recipient matching and outcome of transplantation. The second project is focused upon mechanisms, diagnosis, and pathology of cardiac allograft rejection in man, including the problem of accelerated graft atherosclerosis. Specific protocols are directed toward systematic analysis of the participation of various cellular subpopulations in both peripheral blood and cardiac graft biopsy specimens in the rejection process, serial assessment of recipient cell-mediated cytotoxicity against cultured donor cells, serial monitoring for recipient antibody formation against graft antigens, extensive morphological characterization of early and late postoperative graft rejection as determined by serial biopsy, and analysis of kinetic disturbances in the function of platelets and coagulation factors during acute rejection. The third major project consists of refinement of methodology for production, analysis, and clinical manipulation of heterologous (rabbit) antihuman antithymocyte globulin for control of the immune response, and experimental evaluation of total lymphoid irradiation as an adjunctive immunosuppressive measure. The fourth major project incorporates a broad-based analysis of physiology and pharmacology of the transplanted heart. Specific protocols are directed overall functional capacity of cardiac recipients, analysis of donor left ventricular physiological and electrophysiological responses to cardioactive and vasoactive drugs, and the role of the denervated human heart in reflex mechanisms. The clinical heart transplantation program provides in-depth training to medical and surgical trainees and also constitutes an international demonstration project is cardiac transplantation.